Hepatitis C virus and vaccine development.

The prevalence of Hepatitis C virus (HCV) is approximately 3% around the world. This virus causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The effectiveness of interferon-α and ribavirin therapy is about 50% and is associated with significant toxicity and cost. Hence, generating new vaccines or drugs is an obligation. However, there is no vaccine available for clinical use. DNA vaccines have some advantages such as producing feasibility and generating intensive cellular and humoral immune responses. Activation and improvement of natural immune defense mechanisms is a necessity for the development of an effective HCV vaccine. This article discusses the current status of therapies for hepatitis C, the promising new therapies and the experimental strategies to develop an HCV vaccine.

experience (6). However, toxicity is very important in any experimental therapeutic agent (7). The chronic stage of infection is mainly related to HCV pathogenicity, hence there is a need to improve the ability of a vaccine approach to manage or treat this infection (5). Combination of pegylated interferon (IFN) and ribavirin is the common treatment for HCV. Since this regimen is costly, extended, have severe side-effects and is not efficient sometimes (8). On the other hand, recently researchers have shown that tamoxifen suppressed HCV genome replication in a dose dependent manner (9).
However, there are crucial issues concerning generating HCV vaccines that will have the ability to prevent and/ or treat this infection (10). In this review, we will first demonstrate the current understanding of HCV infection, pathogenicity and therapy methods and then focus our attention on the significant degree of viral diversity which complicates vaccine development.

Molecular analysis of the HCV genome
The HCV genome is a single-stranded RNA which contains a large open reading frame of 9, 030 to 9, 099 bp that could encode a polyprotein of 3, 010 to 3, 033 amino acids (10)(11)(12). Polyprotein cleavage and separate protein production occurs at two sites via host signal peptidase in the structural region and HCV-encoded proteases in the nonstructural (NS) region. The structural region is composed of the core protein and two envelope proteins (E1 and E2) (11). The defined and hypothetical properties of these genomic proteins are shown in Table 1.
The HCV core protein consists of the first structural protein at the amino end of the polyprotein, and performs several activities (13)(14).
During maturation, core protein undergoes two sequential membrane-dependent slicing and two types of core protein (amino acids 1 to C173 and amino acids 1 to C191) are produced. These core protein products have cytoplasmic localization. But in the absence of C191, C173 is capable of translocation into the nucleus (15). E1 and E2 glycoproteins encoded by HCV, are hypothesized to be essential in viral envelope formation (16).
Previous studies have demonstrated that these structural proteins stimulate the production of neutralizing antibodies and they might also serve as future vaccine candidates (17,18). These glycoproteins are supposed to play crucial roles in viral entry by binding to the receptor present on the host and in the virus-host immune interactions (19,20). The NS2 protein is a transmembrane protein anchored to the endoplasmic reticulum with its carboxy terminus while its amino terminus is located in the cytosol (17). Immunoprecipitation investigations (21) revealed that NS2 is closely related to the structural proteins, but the molecular mechanism of action of this protein is poorly understood (3). The HCV non-structural 3 protein (NS3) is a protein of 70 kDa with three known catalytic activities consisting of a serine protease at its N terminus and protease and helicase activities at its C terminus (22). Previous studies showed that NS3 or its fragment may inhibit phosphorylation mediated by cAMP-dependent protein kinase, and  (3). The mechanism of hepatocyte destruction in hepatitis C has been found to be cell-mediated immunity.
HCV evades host antibody-mediated neutralization through high variability of its genomic RNA (32).
When the virus enters hepatocyte cells via receptor mediated endocytosis, then its replication is initiated and hepatocyte destruction starts by subsequent host's immune response (33). Because of complicated functions of HCV genomic proteins, the virus is able to evade the natural interferonmediated clearance (15). HCV infection has been linked to expansion of B lymphocytes in diseases such as mixed-type II cryoglobulinemia (32) and non-Hodgkin's lymphoma (33). Studies showed that CD81-derived signal in B cells can mediate B cell activation and proliferation (34). HCV through its core protein and NS3 induce production of nitric oxide that causes DNA damage and mutations which play an important role in oncogenesis in HCC (35).

Approaches to HCV vaccinedevelopment
There are two major approaches to HCV for vaccine development. One is prophylactic and the other is therapeutic vaccines for clinical use

Peptide vaccines
Class I MHC molecules exist almost in all cell